Increased Regenerative Capacity of the Olfactory Epithelium in Niemann-Pick Disease Type C1.

Anja Meyer,René Günther,Andreas Wree,Oliver Schmitt,Carsten Holzmann,Arndt Rolfs,Martin Witt

doi:10.3390/ijms18040777

Anja Meyer, René Günther + Show 5 more

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https://doi.org/10.3390/ijms18040777

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Abstract

Niemann–Pick disease type C1 (NPC1) is a fatal neurovisceral lysosomal lipid storage disorder. The mutation of the NPC1 protein affects the homeostasis and transport of cholesterol and glycosphingolipids from late endosomes/lysosomes to the endoplasmic reticulum resulting in progressive neurodegeneration. Since olfactory impairment is one of the earliest symptoms in many neurodegenerative disorders, we focused on alterations of the olfactory epithelium in an NPC1 mouse model. Previous findings revealed severe morphological and immunohistochemical alterations in the olfactory system of NPC1−/− mutant mice compared with healthy controls (NPC1+/+). Based on immunohistochemical evaluation of the olfactory epithelium, we analyzed the impact of neurodegeneration in the olfactory epithelium of NPC1−/− mice and observed considerable loss of mature olfactory receptor neurons as well as an increased number of proliferating and apoptotic cells. Additionally, after administration of two different therapy approaches using either a combination of miglustat, 2-hydroxypropyl-β-cyclodextrin (HPβCD) and allopregnanolone or a monotherapy with HPβCD, we recorded a remarkable reduction of morphological damages in NPC1−/− mice and an up to four-fold increase of proliferating cells within the olfactory epithelium. Numbers of mature olfactory receptor neurons doubled after both therapy approaches. Interestingly, we also observed therapy-induced alterations in treated NPC1+/+ controls. Thus, olfactory testing may provide useful information to monitor pharmacologic treatment approaches in human NPC1.

Highlights

Neurodegenerative diseases become increasingly important because of an aging society
The basal layer consists of horizontal and globose basal cells that act as stem and progenitor cells and are responsible for the regeneration of olfactory receptor neurons (ORNs)
We analyzed the regenerative capacity of the olfactory epithelium (OE) in an Niemann–Pick disease type C1 (NPC1)−/− mouse mouse model and the impact of two different therapy approaches with a combination of miglustat, 2-hydroxypropyl-β-cyclodextrin (HPβCD) and allopregnanolone (COMBI) as well as a monotherapy with HPβCD

Summary

Introduction

Neurodegenerative diseases become increasingly important because of an aging society. Olfactory impairment is one of the first symptoms in many neurodegenerative diseases and partly precedes motor symptoms for years. 96% of patients with Parkinson’s disease demonstrate olfactory malfunction up to four years before the clinical onset of motor symptoms [1,2,3]. Alzheimer’s disease is associated with a progressive olfactory impairment in about 90% of the patients [4,5]. Olfactory impairment has a direct influence on the patient’s quality of life and is frequently associated with neurodegenerative diseases, the olfactory system and in particular the olfactory epithelium has not been in the focus of extensive research activities [7,8]. Regulation of olfactory neurogenesis is a multifaceted chain of molecular events leading to adequate proliferation and further differentiation of basal progenitor cells upon challenges of homeostasis during developing neurodegenerative diseases [12,13]

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